bims-amsmem Biomed News
on AMPK signaling mechanism in energy metabolism
Issue of 2022–03–13
39 papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Effects of Thiamin Restriction on Exercise-Associated Glycogen Metabolism and AMPK Activation Level in Skeletal Muscle.
  2. Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK-eNOS-NO pathway.
  3. AMP-activated kinase regulates porcine reproductive and respiratory syndrome virus infection in vitro.
  4. Dendropanax trifidus Sap-Mediated Suppression of Obese Mouse Body Weight and the Metabolic Changes Related with Estrogen Receptor Alpha and AMPK-ACC Pathways in Muscle Cells.
  5. Energy deprivation-induced AMPK activation inhibits milk synthesis by targeting PrlR and PGC-1α.
  6. Resveratrol regulates muscle fiber type gene expression through AMPK signaling pathway and miR-22-3p in porcine myotubes.
  7. Consistency and Synchronization of AMPK-Glycogen in Endometrial Epithelial Cells is Critical to the Embryo Implantation.
  8. Saxagliptin enhances osteogenic differentiation in MC3T3-E1 cells, dependent on the activation of AMP-activated protein kinase α (AMPKα)/runt-related transcription factor-2 (Runx-2).
  9. XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.
  10. Mitigative impact of bradykinin potentiating factor isolated from Androctonus amorexi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through Ang II/AMPK crosstalk.
  11. Clitorin ameliorates western diet-induced hepatic steatosis by regulating lipogenesis and fatty acid oxidation in vivo and in vitro.
  12. Bixin Prevents Colorectal Cancer Development through AMPK-Activated Endoplasmic Reticulum Stress.
  13. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways.
  14. Role of polyphenols in combating Type 2 Diabetes and insulin resistance.
  15. Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin.
  16. Metformin protects against sunitinib-induced cardiotoxicity: Investigating the role of AMPK.
  17. Naringin protects human nucleus pulposus cells against TNF-α-induced inflammation, oxidative stress, and loss of cellular homeostasis by enhancing autophagic flux via AMPK/SIRT1 activation.
  18. Neohesperidin Dihydrochalcone and Neohesperidin Dihydrochalcone-O-Glycoside Attenuate Subcutaneous Fat and Lipid Accumulation by Regulating PI3K/AKT/mTOR Pathway In Vivo and In Vitro.
  19. Role of fruits in aging and age-related disorders.
  20. Bradykinin postconditioning protects rat hippocampal neurons after restoration of spontaneous circulation following cardiac arrest via activation of the AMPK/mTOR signaling pathway.
  21. Dihydromyricetin improves meat quality and promotes skeletal muscle fiber type transformations via AMPK signaling in growing-finishing pigs.
  22. IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
  23. Modulation of Bleomycin-induced oxidative stress and pulmonary fibrosis by ginkgetin in mice via AMPK.
  24. C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood-Retinal Barrier Tight Junctions.
  25. Many roads lead to Rome: The FGF4-AMPK-Caspase 6 signal axis in NAFLD and NASH.
  26. Dapagliflozin attenuates high glucose-induced endothelial cell apoptosis and inflammation through AMPK/SIRT1 activation.
  27. Irisin alleviates vascular calcification by inhibiting VSMC osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling pathway in chronic kidney disease.
  28. Calcium/calmodulin-dependent protein kinase kinase 2 mediates pleiotropic effects of epidermal growth factor in cancer cells.
  29. Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control.
  30. Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.
  31. Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
  32. Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway.
  33. Therapeutic effect and mechanism of polysaccharides from Anoectochilus Roxburghii (Wall.) Lindl. in diet-induced obesity.
  34. TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway.
  35. Recent update on application of dihydromyricetin in metabolic related diseases.
  36. Molecular Mechanism Underlying the Regulatory Effect of Vine Tea on Metabolic Syndrome by Targeting Redox Balance and Gut Microbiota.
  37. (-)-Epicatechin Improves Vasoreactivity and Mitochondrial Respiration in Thermoneutral-Housed Wistar Rat Vasculature.
  38. Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells.
  39. Short-Term Adaptations in Skeletal Muscle Mitochondrial Oxidative Capacity and Metabolic Pathways to Breaking up Sedentary Behaviors in Overweight or Obese Adults.
  1. Nutrients. 2022 Feb 08. pii: 710. [Epub ahead of print]14(3):
    Effects of Thiamin Restriction on Exercise-Associated Glycogen Metabolism and AMPK Activation Level in Skeletal Muscle.
    Akiko Sato, Shinji Sato, Go Omori, Keiichi Koshinaka.
      This study aimed to investigate the direct influence of a decrease in the cellular thiamin level, before the onset of anorexia (one of the symptoms of thiamin deficiency) on glycogen metabolism and the AMP-activated protein kinase (AMPK) activation levels in skeletal muscle at rest and in response to exercise. Male Wistar rats were classified as the control diet (CON) group or the thiamin-deficient diet (TD) group and consumed the assigned diets for 1 week. Skeletal muscles were taken from the rats at rest, those that underwent low-intensity swimming (LIS), or high-intensity intermittent swimming (HIS) conducted immediately before dissection. There were no significant differences in food intake, locomotive activity, or body weight between groups, but thiamin pyrophosphate in the skeletal muscles of the TD group was significantly lower than that of the CON group. Muscle glycogen and lactate levels in the blood and muscle were equivalent between groups at rest and in response to exercise. The mitochondrial content was equal between groups, and AMPK in the skeletal muscles of TD rats was normally activated by LIS and HIS. In conclusion, with a lowered cellular thiamin level, the exercise-associated glycogen metabolism and AMPK activation level in skeletal muscle were normally regulated.
    Keywords:  AMP-activated protein kinase (AMPK); exercise; glycogen; mitochondrial content; thiamin
    DOI:  https://doi.org/10.3390/nu14030710
  2. Sci Rep. 2022 Mar 10. 12(1): 4225
    Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK-eNOS-NO pathway.
    Marta Sanz-Gómez, Elnaz Aledavood, Marina Beroiz-Salaverri, Laura Lagartera, Elena Vega-Martín, Marta Gil-Ortega, Jose Cumella, Concepción Pérez, Francisco Javier Luque, Carolina Estarellas, María S Fernández-Alfonso, Ana Castro.
      Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1β1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK-eNOS-NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.
    DOI:  https://doi.org/10.1038/s41598-022-07077-8
  3. Virus Genes. 2022 Mar 07.
    AMP-activated kinase regulates porcine reproductive and respiratory syndrome virus infection in vitro.
    Jianyu Fang, Hongkui Wang, Limin Lang, Haili Li, Shaoyu Li, Keling Wang.
      Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen in the pig industry worldwide. Many viruses manipulate their cellular metabolism to replicate themselves and cause infection. A conserved cellular energy sensor, 5'-AMP-activated protein kinase (AMPK), maintains cellular energy homeostasis. We found that PRRSV infection caused significant AMPK activation in a time-dependent manner via the ROS-calcium/calmodulin-dependent protein kinase-2 pathway. RNA interference-mediated AMPK knockdown could increase PRRSV replication in MARC-145 cells, suggesting that AMPK contributed to PRRSV infection regulation. Moreover, investigation of the effect of AMPK activity on PRRSV replication showed that PRRSV replication could be suppressed by the pharmacological agonists 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and A769662. Conversely, an AMPK inhibitor, compound C, markedly enhanced PRRSV infection. Furthermore, the AMPK agonist A769662 was found to exert no effect on PRRSV entry, assembly, and release, suggesting that A769662 may hinder the PRRSV genome replication in MARC-145 cells. In conclusion, AMPK may be a promising antiviral drug target against PRRSV infection.
    Keywords:  AMP-activated protein kinase; Phosphorylation; Porcine reproductive and respiratory syndrome; Virus replication and infection
    DOI:  https://doi.org/10.1007/s11262-022-01888-7
  4. Nutrients. 2022 Mar 05. pii: 1098. [Epub ahead of print]14(5):
    Dendropanax trifidus Sap-Mediated Suppression of Obese Mouse Body Weight and the Metabolic Changes Related with Estrogen Receptor Alpha and AMPK-ACC Pathways in Muscle Cells.
    Ahreum Lee, Eugene Koh, Dalnim Kim, Namkyu Lee, Soo Min Cho, Young Joo Lee, Ik-Hyun Cho, Hyun-Jeong Yang.
      Dendropanax trifidus (DT) is a medicinal herb native to East Asia, which has been used extensively for its therapeutic properties in traditional medicine. In this study, we examined the effects of DT sap on the regulation of body weight and muscle metabolism in mice. Obese model db/db mice were administered daily with DT sap or vehicle control over a 6-week period. The effects of DT sap on muscle metabolism were studied in C2C12 muscle cells, where glycolytic and mitochondrial respiration rates were monitored. As AMP-activated protein kinase (AMPK) is a master regulator of metabolism and plays an important function as an energy sensor in muscle tissue, signaling pathways related with AMPK were also examined. We found that DT sap inhibited body weight increase in db/db, db/+, and +/+ mice over a 6-week period, while DT sap-treated muscle cells showed increased muscle metabolism and also increased phosphorylation of AMPK and Acetyl-CoA Carboxylase (ACC). Finally, we found that DT sap, which is enriched in estrogen in our previous study, significantly activates estrogen alpha receptor in a concentration-dependent manner, which can drive the activation of AMPK signaling and may be related to the muscle metabolism and weight changes observed here.
    Keywords:  ACC; AMPK; C2C12; Dendropanax trifidus; body weight; estrogen; glycolysis; metabolism; mitochondrial respiration
    DOI:  https://doi.org/10.3390/nu14051098
  5. Cell Commun Signal. 2022 Mar 05. 20(1): 25
    Energy deprivation-induced AMPK activation inhibits milk synthesis by targeting PrlR and PGC-1α.
    Zhihui Wu, Qihui Li, Siwang Yang, Tenghui Zheng, Jiayuan Shao, Wutai Guan, Fang Chen, Shihai Zhang.
       BACKGROUND: The mammary gland is responsible for milk production and secretion, which is critical for neonatal health during lactation. Lactation efficiency is largely affected by energy status with unclear mechanism.
    RESULTS: In the current study, we found that synthesis of milk fat and protein was significantly inhibited under energy-deficient conditions, which is accompanied with AMP-activated protein kinase (AMPK) activation. Modulating the AMPK signaling pathway directly or indirectly affects the synthesis of milk fat and protein. Besides mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of milk synthesis, we discovered that AMPK mainly regulates the synthesis of milk protein through prolactin signaling. Mechanistically, AMPK triggers the ubiquitination of prolactin receptor (PrlR) through regulating the activity of β-transducin repeat-containing protein (β-TrCP, an E3 ligase). Subsequently, PrlR is degraded by the endocytosis process of lysosomes, which further attenuates prolactin signaling. In addition, our results revealed that AMPK activation inhibits milk fat synthesis through decreasing and accelerating de novo synthesis and β-oxidation of fatty acids, respectively. To be precise, AMPK activation inhibits rate limiting enzymes and transcriptional regulatory factors involved in de novo fatty acid synthesis and decreases the acetylation process of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) to strengthen the oxidation of fatty acids.
    CONCLUSIONS: Taken together, AMPK regulates the synthesis of milk not only depends on canonical mTORC1 signaling and key rate-limiting enzymes, but also through manipulating the degradation of PrlR and the acetylation of PGC-1α. Video Abstract.
    Keywords:  AMPK; Mammary epithelial cells; Milk fat; Milk protein; PGC-1α; PrlR
    DOI:  https://doi.org/10.1186/s12964-022-00830-6
  6. Anim Biotechnol. 2022 Mar 10. 1-7
    Resveratrol regulates muscle fiber type gene expression through AMPK signaling pathway and miR-22-3p in porcine myotubes.
    Wanxue Wen, Xiaoling Chen, Zhiqing Huang, Daiwen Chen, Bing Yu, Jun He, Hui Yan, Yuheng Luo, Hong Chen, Ping Zheng, Jie Yu.
      This study aimed to investigate the effect and underlying mechanisms of resveratrol on porcine muscle fiber type gene expression in porcine myotubes. Here, results showed that resveratrol treatment significantly promoted slow myosin heavy chain (MyHC) and inhibited fast MyHC in porcine myotubes. The phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and the downstream factors of AMPK signaling, such as Sirtuin1 (Sirt1) and peroxlsome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), were also increased by resveratrol, suggesting that resveratrol could activate the AMPK signaling pathway. Interestingly, resveratrol inhibited the expression of miR-22-3p in porcine myotubes. Furthermore, AMPK inhibitor compound C and miR-22-3p mimic effectively eliminated the effects of resveratrol on slow MyHC and fast MyHC expressions in porcine myotubes. Taken together, our findings indicate that resveratrol regulates muscle fiber type gene expression through the AMPK signaling pathway and miR-22-3p in porcine myotubes.
    Keywords:  AMPK signaling pathway; Resveratrol; miR-22-3p; muscle fiber type gene expression; porcine myotubes
    DOI:  https://doi.org/10.1080/10495398.2022.2046599
  7. Reproduction. 2022 Mar 01. pii: REP-21-0382. [Epub ahead of print]
    Consistency and Synchronization of AMPK-Glycogen in Endometrial Epithelial Cells is Critical to the Embryo Implantation.
    Li Nie, Li-Xue Zhang, Yi-Cheng Wang, Yun Long, Yong-Dan Ma, Lin-Chuan Liao, Xin-Hua Dai, Zhi-Hui Cui, Huan Liu, Zhaoqi Wang, Ziyang Ma, Dongzhi Yuan, Li-Min Yue.
      Uterine receptivity to the embryo is crucial for successful implantation. The establishment of uterine receptivity requires a large amount of energy, and abnormal energy regulation causes implantation failure. Glucose metabolism in the endometrium is tissue specific. Glucose is largely stored in the form of glycogen, which is the main energy source for the endometrium. AMP-activated protein kinase (AMPK), an important energy-sensing molecule, is a key player in the regulation of glucose metabolism, and its regulation is also tissue specific. However, the mechanism of energy regulation in the endometrium for the establishment of uterine receptivity remains to be elucidated. In this research, we aimed to investigate the energy regulation mechanism of mouse uterine receptivity and its significance in embryo implantation. The results showed that the AMPK, p-AMPK, glycogen synthase 1, and glycogen phosphorylase M levels and the glycogen content in mouse endometrial epithelium varied in a periodic manner under regulation by the ovarian hormone. Specifically, progesterone significantly activated AMPK, promoted glycogenolysis, and upregulated glycogen phosphorylase M expression. AMPK regulated glycogen phosphorylase M expression and promoted glycogenolysis. AMPK was also found to be activated by changes in the energy or glycogen of the endometrial epithelial cells. The inhibition of AMPK activity or glycogenolysis altered the uterine receptivity markers during the window of implantation and ultimately interfered with implantation. In summary, consistency and synchronization of AMPK and glycogen metabolism constitute the core regulatory mechanism in mouse endometrial epithelial cells involved in the establishment of uterine receptivity.
    DOI:  https://doi.org/10.1530/REP-21-0382
  8. Bioengineered. 2022 Jan;13(1): 431-439
    Saxagliptin enhances osteogenic differentiation in MC3T3-E1 cells, dependent on the activation of AMP-activated protein kinase α (AMPKα)/runt-related transcription factor-2 (Runx-2).
    Qiang Wang, Xiaoxing Xie, Dehua Zhang, Feng Mao, Shaobo Wang, Yi Liao.
      Osteoporosis is a metabolic bone disease commonly observed in the elderly, and its pathogenesis is associated with declined osteogenic differentiation. Osteogenic differentiation could be facilitated by the activation of the AMP-activated protein kinase (AMPK) pathway. Saxagliptin, an anti-diabetic agent with inhibitory effects against dipeptidyl peptidase 4 (DPP-4), has been recently reported to induce the activation of the AMPK pathway. The present study proposes to explore the function and mechanism of Saxagliptin in osteogenic differentiation. Osteogenic differentiation induction medium (ODIM) was utilized to induce osteogenic differentiation in MC3T3-E1 cells. Significantly increased mineral nodule formation, elevated alkaline phosphatase (ALP) activity, and upregulated expression of osteogenic marker genes activating transcription factor-4 (ATF-4), osteopontin (OPN), and type I collagen (Col1) were observed in ODIM-cultured MC3T3-E1 cells, all of which were further enhanced by the introduction of Saxagliptin. The elevated expression level of runt-related transcription factor-2 (Runx-2), an important transcriptional factor involved in the progression of osteogenic differentiation, in ODIM-cultured MC3T3-E1 cells was further promoted by Saxagliptin. The AMPK pathway in ODIM-cultured MC3T3-E1 cells was significantly activated by Saxagliptin, and the functions of Saxagliptin in promoting osteogenic differentiation were abolished by compound C, the inhibitor of the AMPK pathway. Conclusively, Saxagliptin enhanced osteogenic differentiation in MC3T3-E1 cells, dependent on the activation of AMPKα/RUNX-2.
    Keywords:  AMPK; Saxagliptin; osteogenic differentiation; osteoporosis
    DOI:  https://doi.org/10.1080/21655979.2021.2008667
  9. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac013
    XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.
    Min-Goo Lee, Zisun Choi, Na-Jung Lim, Ji-Sun Lim, Kyung-Woo Lee, Kyung-Phil Ko, Byung-Kyu Ryu, Shin-Hyuk Kang, Sung-Gil Chi.
       Background: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human cancers. However, its role in the pathogenesis and therapeutic response of glioma is poorly characterized.
    Methods: XAF1 activation by temozolomide (TMZ) and its effect on TMZ cytotoxicity were defined using luciferase reporter, flow cytometry, and immunofluorescence assays. Signaling mechanism was analyzed using genetic and pharmacologic experiments. In vivo studies were performed in mice to validate the role of XAF1 in TMZ therapy.
    Results: Epigenetic alteration of XAF1 is frequent in cell lines and primary tumors and contributes to cancer cell growth. XAF1 transcription is activated by TMZ via JNK-IRF-1 signaling to promote apoptosis while it is impaired by promoter hypermethylation. In tumor cells expressing high O 6-methylguanine-DNA methyltransferase (MGMT), XAF1 response to TMZ is debilitated. XAF1 facilitates TMZ-mediated autophagic flux to direct an apoptotic transition of protective autophagy. Mechanistically, XAF1 is translocated into the mitochondria to stimulate reactive oxygen species (ROS) production and ataxia telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK) signaling. A mutant XAF1 lacking the zinc finger 6 domain fails to localize in the mitochondria and activate ROS-ATM-AMPK signaling and autophagy-mediated apoptosis. XAF1-restored xenograft tumors display a reduced growth rate and enhanced therapeutic response to TMZ, which is accompanied with activation of ATM-AMPK signaling. XAF1 expression is associated with overall survival of TMZ treatment patients, particularly with low MGMT cancer.
    Conclusions: This study uncovers an important role for the XAF1-ATM-AMPK axis as a linchpin to govern glioma response to TMZ therapy.
    Keywords:  AMPK; XAF1; apoptosis; glioblastoma; temozolomide
    DOI:  https://doi.org/10.1093/noajnl/vdac013
  10. Toxicol Mech Methods. 2022 Mar 06. 1-33
    Mitigative impact of bradykinin potentiating factor isolated from Androctonus amorexi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through Ang II/AMPK crosstalk.
    Hesham Farouk Hasan, Shereen Mohamed Galal, Rania A Ellethy.
      In this study, the mitigative impact of bradykinin potentiating factor (BPF) and low doses of γ-irradiation (LDR) were evaluated against doxorubicin (DOX) hepatotoxicity through Ang II/AMPK crosstalk. Rats have received a single dose of DOX (10 mg/kg, i.p.). BPF administration at a dose of (1 μg/g, b.wt./twice a week), was started one week before the administration of DOX and followed throughout the study for another consecutive week where LDR rats were subjected to 2 low fractions of γ-irradiation; 0.5 Gy/fraction/week up to the cumulative dose of 1 Gy at 7 days before and after doxorubicin administration. DOX produced a remarkable disturbance in serum hepatic enzymes activities, hepatic oxidative stress indices, as well as hepatic inflammatory and fibrotic markers in response to a marked elevation in hepatic angiotensin II (Ang II) together with marked depression in hepatic AMP-activated protein kinase (AMPK) expressions. The combination of BPF and LDR produced a significant improvement in all examined parameters as well as mitigates hepatic toxicity through inhibition of Ang II induced by DOX, which might also be mediated by AMPK activation. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. In conclusion, these findings shed new light on the mechanism underlying the anti-inflammatory and anti-fibrosis consequence of our remedy and support the potential use of it as a preventive and therapeutic candidate against hepatic toxicity through Ang II/AMPK crosstalk.
    Keywords:  AMPK; Ang II; BPF; Doxorubicin; LDR
    DOI:  https://doi.org/10.1080/15376516.2022.2049941
  11. Sci Rep. 2022 Mar 09. 12(1): 4154
    Clitorin ameliorates western diet-induced hepatic steatosis by regulating lipogenesis and fatty acid oxidation in vivo and in vitro.
    Divina C Cominguez, Yea-Jin Park, Yun-Mi Kang, Agung Nugroho, Suhyun Kim, Hyo-Jin An.
      Nonalcoholic fatty liver disease (NAFLD) is usually correlated with metabolic diseases, such as obesity, insulin resistance, and hyperglycemia. Herein, we investigated the inhibitory effects and underlying governing mechanism of clitorin in a western diet (WD)-induced hepatic steatosis mouse model, and in oleic acid-stimulated HepG2 cells. Male C57BL/6 mice were fed a normal diet, WD, WD + 10 or 20 mg/kg orlistat, and WD + 10 or 20 mg/kg clitorin. HepG2 cells were treated with 1 mM oleic acid to induce lipid accumulation with or without clitorin. Clitorin significantly alleviated body weight gain and hepatic steatosis features (NAFLD activity score, micro-, and macro-vesicular steatosis) in WD-induced hepatic steatosis mice. Additionally, clitorin significantly decreased protein expressions of sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor γ (PPARγ), and CCAAT/enhancer binding protein α (C/EBPα) in WD-induced hepatic steatosis mice. Moreover, clitorin significantly diminished the mRNA levels of SREBP1, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and enhanced the mRNA levels of peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltranserase-1 (CTP-1), as well as adenosine monophosphate-activated protein kinase (AMPK) in the liver of WD-induced hepatic steatosis mice and oleic acid-stimulated HepG2 cells. Overall, our findings demonstrated that clitorin can be a potentially efficacious candidate for NAFLD management.
    DOI:  https://doi.org/10.1038/s41598-022-07937-3
  12. Biomed Res Int. 2022 ;2022 9329151
    Bixin Prevents Colorectal Cancer Development through AMPK-Activated Endoplasmic Reticulum Stress.
    Yunfeng Qiu, Changfeng Li, Bin Zhang.
      Chemicals isolated from natural products have been broadly applied in the treatment of colorectal cancer (CRC). Bixin, an apocarotenoid from the seeds of Bixa orellana, exerts multiple pharmacological properties, including neuroprotective, anti-inflammatory, cardioprotective, and antitumor effects; yet, the therapeutic effects of Bixin on CRC are still unknown. Here, we described that Bixin treatment significantly inhibited the proliferation and motility of two CRC cell lines (CaCO2 and SW480) in vitro and in vivo. In addition, Bixin administration has sensitized CRC cells to TNF-related apoptosis-inducing ligand- (TRAIL-) induced cell apoptosis. Moreover, we showed that Bixin treatment initiated the activation of PERK/eIF-2α signal in CaCO2 and SW480 cells, leading to endoplasmic reticulum stress-associated apoptosis. Pharmacological inhibition of AMP-activated protein kinase (AMPK) abrogated the Bixin-induced activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF-2α) pathway, as well as reversed the inhibitory effects of Bixin on CRC development. In conclusion, this study indicated that Bixin treatment inhibits the progression of CRC through activating the AMPK/PERK/eIF-2α pathway, providing a novel potential strategy for clinical prevention of CRC.
    DOI:  https://doi.org/10.1155/2022/9329151
  13. Acta Pharm Sin B. 2022 Feb;12(2): 708-722
    Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways.
    Xiang Wang, Xinxin Chen, Wenqian Zhou, Hongbo Men, Terigen Bao, Yike Sun, Quanwei Wang, Yi Tan, Bradley B Keller, Qian Tong, Yang Zheng, Lu Cai.
      Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
    Keywords:  AMPK; Advanced glycation end-products; Cell death; Diabetic cardiomyopathy; Engineered cardiac tissue; Ferroptosis; Lipid peroxidation; NRF2
    DOI:  https://doi.org/10.1016/j.apsb.2021.10.005
  14. Int J Biol Macromol. 2022 Mar 02. pii: S0141-8130(22)00454-8. [Epub ahead of print]206 567-579
    Role of polyphenols in combating Type 2 Diabetes and insulin resistance.
    Moyad Shahwan, Fahad Alhumaydhi, Ghulam Md Ashraf, Prince M Z Hasan, Anas Shamsi.
      Compromised carbohydrate metabolism leading to hyperglycemia is the primary metabolic disorder of non-insulin-dependent diabetes mellitus. Reformed digestion and altered absorption of carbohydrates, exhaustion of glycogen stock, enhanced gluconeogenesis and overproduced hepatic glucose, dysfunction of β-cell, resistance to insulin in peripheral tissue, and impaired insulin signaling pathways are essential reasons for hyperglycemia. Although oral anti-diabetic drugs like α-glucosidase inhibitors, sulfonylureas and insulin therapies are commonly used to manage Type 2 Diabetes (T2D) and hyperglycemia, natural compounds in diet also play a significant role in combating the effect of diabetes. Due to their vast bioavailability and anti-hyperglycemic effect with least or no side effects, polyphenolic compounds have gained wide popularity. Polyphenols such as flavonoids and tannins play a significant role in carbohydrate metabolism by inhibiting key enzymes responsible for the digestion of carbohydrates to glucose, viz. α-glucosidase and α-amylase. Several polyphenols such as resveratrol, epigallocatechin-3-gallate (EGCG) and quercetin enhanced glucose uptake in the muscles and adipocytes by translocating GLUT4 to plasma membrane mainly by the activation of the AMP-activated protein kinase (AMPK) pathway. This review provides an insight into the protective role of polyphenols in T2D, highlighting the aspects of insulin resistance.
    Keywords:  Insulin resistance; Polyphenols; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.03.004
  15. Nutrients. 2022 Jan 28. pii: 583. [Epub ahead of print]14(3):
    Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin.
    Laurence Kay, Lucia Potenza, Isabelle Hininger-Favier, Hubert Roth, Stéphane Attia, Cindy Tellier, Christian Zuppinger, Cinzia Calcabrini, Piero Sestili, Theo Wallimann, Uwe Schlattner, Malgorzata Tokarska-Schlattner.
      Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.
    Keywords:  adenosine 5′-monopnophosphate-activated protein kinase; anthracyclines; cardiac signaling; cardiotoxicity; creatine supplementation; doxorubicin; soy; vegetarian/vegan diet
    DOI:  https://doi.org/10.3390/nu14030583
  16. J Cardiovasc Pharmacol. 2022 Mar 08.
    Metformin protects against sunitinib-induced cardiotoxicity: Investigating the role of AMPK.
    Refik Kuburas, Mayel Gharanei, Irmgard Haussmann, Helen Maddock, Hardip Sandhu.
       ABSTRACT: Sunitinib is associated with cardiotoxicity through inhibition of AMP-protein kinase (AMPK) signalling. In contrast, the common anti-diabetic agent metformin has demonstrated cardioprotection via indirect AMPK activation. Here we investigate the effects of metformin during sunitinib-induced cytotoxicity. Left ventricular developed pressure (LVDP), coronary flow (CF), heart rate (HR) and infarct size was measured in Langendorff perfused rat hearts treated with 1 µM sunitinib ± 50 µM metformin ± 1 µM human equilibrative nucleoside transporter inhibitor S-(4-Nitrobenzyl)-6-thionosine (NBTI). Western blot analysis was carried out for p-AMPKα levels. Primary isolated cardiac myocytes from the left ventricular tissue were used to measure live cell population levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess adjunctive treatment of and metformin in human hepatoma G2 (HepG2) and promyelocytic leukaemia (HL-60) cells treated with 0.1-100 µM sunitinib ± 50 µM metformin. In the perfused hearts co-administration of metformin attenuated the sunitinib-induced changes to LVDP, infarct size and cardiac myocyte population. Western blot analysis revealed a significant decrease in p-AMPKα during sunitinib treatment, which was attenuated following co-administration with metformin. All metformin-induced effects were attenuated NBTI was co-administered. The MTT assay demonstrated an increase in the EC50-value during co-administration of metformin with sunitinib compared to sunitinib mono-therapy in HepG2 and HL-60 cell lines, demonstrating the impact and complexity of metformin co-administration and the possible role of AMPK signalling. This study highlights the novel cardioprotective properties of metformin and AMPK activation during sunitinib-induced cardiotoxicity when administered together in the Langendorff heart model.
    DOI:  https://doi.org/10.1097/FJC.0000000000001256
  17. Oxid Med Cell Longev. 2022 ;2022 7655142
    Naringin protects human nucleus pulposus cells against TNF-α-induced inflammation, oxidative stress, and loss of cellular homeostasis by enhancing autophagic flux via AMPK/SIRT1 activation.
    Renchang Chen, Shang Gao, Huapeng Guan, Xin Zhang, Yuliang Gao, Youxiang Su, Yun Song, Yuehua Jiang, Nianhu Li.
      Activation of the proinflammatory-associated cytokine, tumor necrosis factor-α (TNF-α), in nucleus pulposus (NP) cells is essential for the pathogenesis of intervertebral disc degeneration (IDD). Restoring autophagic flux has been shown to effectively protect against IDD and is a potential target for treatment. The goal of this study was to explore particular autophagic signalings responsible for the protective effects of naringin, a known autophagy activator, on human NP cells. The results showed that significantly increased autophagic flux was observed in NP cells treated with naringin, with pronounced decreases in the inflammatory response and oxidative stress, which rescued the disturbed cellular homeostasis induced by TNF-α activation. Autophagic flux inhibition was detectable in NP cells cotreated with 3-methyladenine (3-MA, an autophagy inhibitor), partially offsetting naringin-induced beneficial effects. Naringin promoted the expressions of autophagy-associated markers via SIRT1 (silent information regulator-1) activation by AMPK (AMP-activated protein kinase) phosphorylation. Either AMPK inhibition by BML-275 or SIRT1 silencing partially counteracted naringin-induced autophagic flux enhancement. These findings indicate that naringin boosts autophagic flux through SIRT1 upregulation via AMPK activation, thus protecting NP cells against inflammatory response, oxidative stress, and impaired cellular homeostasis. Naringin can be a promising inducer of restoration autophagic flux restoration for IDD.
    DOI:  https://doi.org/10.1155/2022/7655142
  18. Nutrients. 2022 Mar 04. pii: 1087. [Epub ahead of print]14(5):
    Neohesperidin Dihydrochalcone and Neohesperidin Dihydrochalcone-O-Glycoside Attenuate Subcutaneous Fat and Lipid Accumulation by Regulating PI3K/AKT/mTOR Pathway In Vivo and In Vitro.
    Minseo Kwon, Yerin Kim, Jihye Lee, John A Manthey, Yang Kim, Yuri Kim.
      Neohesperidin dihydrochalcone (NHDC), a semi-natural compound from bitter orange, is an intense sweetener. The anti-obesity effects of NHDC and its glycosidic compound, NHDC-O-glycoside (GNHDC), were investigated. C57BLKS/J db/db mice were supplemented with NHDC or GNHDC (100 mg/kg b.w.) for 4 weeks. Body weight gain, subcutaneous tissues, and total adipose tissues (sum of perirenal, visceral, epididymal, and subcutaneous adipose tissue) were decreased in the NHDC and GNHDC groups. Fatty acid uptake, lipogenesis, and adipogenesis-related genes were decreased, whereas β-oxidation and fat browning-related genes were up-regulated in the sweetener groups. Furthermore, both sweeteners suppressed the level of triacylglycerol accumulation, lipogenesis, adipogenesis, and proinflammatory cytokines in the 3T3-L1 cells. The PI3K/AKT/mTOR pathway was also down-regulated, and AMP-acttvated protein kinase (AMPK) was phosphorylated in the treatment groups. These results suggest that NHDC and GNHDC inhibited subcutaneous fat and lipid accumulation by regulating the PI3K/AKT/mTOR pathway and AMPK-related lipogenesis and fat browning.
    Keywords:  PI3K/AKT/mTOR; glycoside; lipogenesis; neohesperidin dihydrochalcone; obesity; subcutaneous adipose tissue
    DOI:  https://doi.org/10.3390/nu14051087
  19. Exp Gerontol. 2022 Mar 03. pii: S0531-5565(22)00071-7. [Epub ahead of print]162 111763
    Role of fruits in aging and age-related disorders.
    Muhammad Usman Arif, Muhammad Kashif Iqbal Khan, Sana Riaz, Akmal Nazir, Abid Aslam Maan, Usman Amin, Farhan Saeed, Muhammad Afzaal.
      Aging is a collection of changes that contribute to decline in maximum function and ultimately death of an organism. This process is controlled and initiated by several mechanisms including telomere shortening, oxidative stress, AMP-activated protein kinase and sirt-1. Several therapies have been reported to relieve the process of aging. Among these, diet therapy seems to be the most appropriate approach. Fruits are an important part of regular diet. They contain several compounds which have potential to handle the problem of aging and its related disorders. The present paper provides a comprehensive review on different factors present in various fruits related to the process of aging together with their antiaging mechanisms.
    Keywords:  AMPK; Aging; Oxidative stress; Reactive oxygen spices; Sirt 1; Telomere
    DOI:  https://doi.org/10.1016/j.exger.2022.111763
  20. Neural Regen Res. 2022 Oct;17(10): 2232-2237
    Bradykinin postconditioning protects rat hippocampal neurons after restoration of spontaneous circulation following cardiac arrest via activation of the AMPK/mTOR signaling pathway.
    Shi-Rong Lin, Qing-Ming Lin, Yu-Jia Lin, Xin Qian, Xiao-Ping Wang, Zheng Gong, Feng Chen, Bin Song.
      Bradykinin (BK) is an active component of the kallikrein-kinin system that has been shown to have cardioprotective and neuroprotective effects. We previously showed that BK postconditioning strongly protects rat hippocampal neurons upon restoration of spontaneous circulation (ROSC) after cardiac arrest. However, the precise mechanism underlying this process remains poorly understood. In this study, we treated a rat model of ROSC after cardiac arrest (induced by asphyxiation) with 150 μg/kg BK via intraperitoneal injection 48 hours after ROSC following cardiac arrest. We found that BK postconditioning effectively promoted the recovery of rat neurological function after ROSC following cardiac arrest, increased the amount of autophagosomes in the hippocampal tissue, inhibited neuronal cell apoptosis, up-regulated the expression of autophagy-related proteins LC3 and NBR1 and down-regulated p62, inhibited the expression of the brain injury marker S100β and apoptosis-related protein caspase-3, and affected the expression of adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway-related proteins. Adenosine monophosphate-activated protein kinase inhibitor compound C clearly inhibited BK-mediated activation of autophagy in rats after ROSC following cardiac arrest, which aggravated the injury caused by ROSC. The mechanistic target of rapamycin inhibitor rapamycin enhanced the protective effects of BK by stimulating autophagy. Our findings suggest that BK postconditioning protects against injury caused by ROSC through activating the adenosine monophosphate-activated protein kinase/mechanistic target of the rapamycin pathway.
    Keywords:  autophagy; bradykinin; cardiac arrest; cardiopulmonary resuscitation; compound C; hippocampus; neuron; rapamycin; restoration of spontaneous circulation
    DOI:  https://doi.org/10.4103/1673-5374.337049
  21. Food Funct. 2022 Mar 09.
    Dihydromyricetin improves meat quality and promotes skeletal muscle fiber type transformations via AMPK signaling in growing-finishing pigs.
    Zhongyang Guo, Xiaoling Chen, Zhiqing Huang, Daiwen Chen, Mingzhou Li, Bing Yu, Jun He, Yuheng Luo, Hui Yan, Ping Zheng.
      As the demand of consumers for good meat quality is increasing, there is more interest in improving pork quality by nutritional regulation. Dihydromyricetin (DHM), a group of bioactive flavonoids, exhibits excellent biological functions and pharmacological activities. This study aimed to investigate whether dietary DHM supplementation in growing-finishing pigs could provide high-quality pork. A total of 24 healthy castrated Duroc × Landrace × Yorkshire (DLY) pigs with an average body weight of 26.95 ± 0.26 kg were randomly divided into four groups (basal diet and a basal diet supplemented with 100, 300 and 500 mg kg-1 DHM) with 6 duplicates and one pig per replicate. The growth performance, carcass traits and pork quality of growing-finishing pigs were detected. Then, tandem mass tag (TMT) based quantitative proteomics, western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were used to explore the regulatory mechanism of DHM on pork quality. The results showed that DHM decreased the feed to gain ratio (F/G) and improved the sensory quality (shear force and meat color) and nutritional value (crude protein content and amino acid composition) of pork in growing-finishing pigs. Totally 22 differentially expressed proteins were identified, among which the down-regulated heat shock protein-β1 (HSPB1) and up-regulated Troponin C-slow (TNNC1) contributed towards explaining the positive effect of DHM on the tenderness and meat color of pork. GO enrichment analysis revealed that better meat color was also linked to higher levels of oxidative metabolism and hemoglobin complexes in pork. Western blotting and RT-qPCR analysis showed that DHM induced a muscle fiber type transformation from fast-switch to slow-switch by activating the AMP-activated protein kinase (AMPK) signal, thereby improving the pork quality. Taken together, our findings provide effective evidence for the application of DHM in high-quality pork production.
    DOI:  https://doi.org/10.1039/d1fo03391c
  22. Acta Pharm Sin B. 2022 Feb;12(2): 651-664
    IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
    Juan Liu, Yuxin Zhuang, Jianlin Wu, Qiang Wu, Meixian Liu, Yue Zhao, Zhongqiu Liu, Caiyan Wang, Linlin Lu, Yingjiao Meng, Kawai Lei, Xiaojuan Li, Qibiao Wu, Elaine Lai-Han Leung, Zhengyang Guo, Liang Liu, Ting Li.
      Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is one of important kinases in inflammation to phosphorylate inhibitor of nuclear factor kappa-B (IκBα) and then activate nuclear factor kappa-B (NF-κB). Inhibition of IKKβ has been a therapeutic strategy for inflammatory and autoimmune diseases. Here we report that IKKβ is constitutively activated in healthy donors and healthy Ikkβ C46A (cysteine 46 mutated to alanine) knock-in mice although they possess intensive IKKβ-IκBα-NF-κB signaling activation. These indicate that IKKβ activation probably plays homeostatic role instead of causing inflammation. Compared to Ikkβ WT littermates, lipopolysaccharides (LPS) could induce high mortality rate in Ikkβ C46A mice which is correlated to breaking the homeostasis by intensively activating p-IκBα-NF-κB signaling and inhibiting phosphorylation of 5' adenosine monophosphate-activated protein kinase (p-AMPK) expression. We then demonstrated that IKKβ kinase domain (KD) phosphorylates AMPKα1 via interacting with residues Thr183, Ser184, and Thr388, while IKKβ helix-loop-helix motifs is essential to phosphorylate IκBα according to the previous reports. Kinase assay further demonstrated that IKKβ simultaneously catalyzes phosphorylation of AMPK and IκBα to mediate homeostasis. Accordingly, activation of AMPK rather than inhibition of IKKβ could substantially rescue LPS-induced mortality in Ikkβ C46A mice by rebuilding the homeostasis. We conclude that IKKβ activates AMPK to restrict inflammation and IKKβ mediates homeostatic function in inflammation via competitively phosphorylating AMPK and IκBα.
    Keywords:  AMPK; Anti-inflammatory drug; Homeostasis; IKKβ; Inflammation; IκBα; Kinase domain; Phosphorylation
    DOI:  https://doi.org/10.1016/j.apsb.2021.09.012
  23. Curr Mol Pharmacol. 2022 Mar 04.
    Modulation of Bleomycin-induced oxidative stress and pulmonary fibrosis by ginkgetin in mice via AMPK.
    Guoqing Ren, Gonghao Xu, Renshi Li, Haifeng Xie, Zhengguo Cui, Lei Wang, Chaofeng Zhang.
       BACKGROUND: Ginkgetin, a flavonoid extracted from ginkgo biloba, has been shown to exhibit broad anti-inflammatory, anticancer, and antioxidative bioactivity. The extract of Ginkgo folium has been reported on attenuating bleomycin-induced pulmonary fibrosis, but the anti-fibrotic effects of ginkgetin is still unclear. This study was intended to investigate the protective effects of ginkgetin against experimental pulmonary fibrosis and its underlying mechanism.
    METHODS: In vivo, bleomycin (5 mg/kg) in 50 μL saline was administrated intratracheally in mice. One week after bleomycin administration, ginkgetin (25 or 50 mg/kg) or nintedanib (40 mg/kg) were administrated intragastrically daily for 14 consecutive days. In vitro, the AMPK-siRNA transfection in primary lung fibroblasts further verified the regulation effect of ginkgetin on AMPK.
    RESULTS: Administration of bleomycin caused characteristic histopathology structural changes with elevated lipid peroxidation, pulmonary fibrosis indexes, and inflammatory mediators. The bleomycin-induced alteration was normalized by ginkgetin intervention. Moreover, this protective effect of ginkgetin (20 mg/kg) was equivalent to nintedanib (40 mg/kg). AMPK-siRNA transfection in primary lung fibroblasts markedly blocked TGF-1-induced myofibroblasts transdifferentiation and abolished oxidative stress.
    CONCLUSIONS: All these results suggested that ginkgetin exerted the ameliorative effects on bleomycin-induced oxidative stress and lung fibrosis mainly through an AMPK-dependent manner.
    Keywords:  AMPK; Ginkgetin; NADPH Oxidase 4; Oxidative stress; Pulmonary fibrosis; Sirtuin 1
    DOI:  https://doi.org/10.2174/1874467215666220304094058
  24. Cells. 2022 Feb 23. pii: 779. [Epub ahead of print]11(5):
    C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood-Retinal Barrier Tight Junctions.
    Zheyi Yan, Chunfang Wang, Zhijun Meng, Lu Gan, Rui Guo, Jing Liu, Wayne Bond Lau, Dina Xie, Jianli Zhao, Bernard L Lopez, Theodore A Christopher, Ulhas P Naik, Xinliang Ma, Yajing Wang.
      Background The impairment of the inner blood-retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood-retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood-retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR.
    Keywords:  CTRP3; diabetic retinopathy; iBRB; permeability; tight junction proteins
    DOI:  https://doi.org/10.3390/cells11050779
  25. Hepatology. 2022 Mar 12.
    Many roads lead to Rome: The FGF4-AMPK-Caspase 6 signal axis in NAFLD and NASH.
    Alena Laschtowitz, Frank Tacke.
      
    DOI:  https://doi.org/10.1002/hep.32454
  26. Clin Exp Pharmacol Physiol. 2022 Mar 11.
    Dapagliflozin attenuates high glucose-induced endothelial cell apoptosis and inflammation through AMPK/SIRT1 activation.
    Yousef Faridvand, Hamid Kazemzadeh, Vahid Vahedian, Pourya Mirzajanzadeh, Hamid Reza Nejabati, Nasser Safaie, Nazila Fathi Maroufi, Masoud Pezeshkian, Mohammad Nouri, Ahmadreza Jodati.
      Hyperglycemia is a major cause of pathophysiological processes such as oxidative stress, inflammation, and apoptosis in diabetes. Dapagliflozin (DAPA), a novel hypoglycemic drug, has been shown to have anti-apoptotic, anti-inflammatory, and antioxidant effects in multiple experimental studies. In this study, we investigated the protective effects of DAPA in the hyperglycemic condition to identify associated molecular mechanisms. HUVEC endothelial cells were treated with 40 mM glucose for 72h to establish in vitro high glucose (HG) condition model, and then additional groups co-treated with or without DAPA before glucose treatment. Then, cell viability, reactive oxygen species (ROS), proinflammatory cytokines (IL-6 and TNF-α), apoptosis, and SIRT1 expression were measured. The results showed that DAPA pretreatment resulted in increased cell viability. Additionally, DAPA pretreatment decreased endothelial ROS, IL-6, and TNF-α levels in endothelial cells subjected to HG conditions. Moreover, DAPA pretreatment significantly prevented HG-induced apoptosis and caspase-3 activity in HUVECs. Furthermore, DAPA increased the expression of SIRT1, PGC-1α, and increased the phosphorylation levels of AMPK (p-AMPK) in a set of HG conditions in HUVEC cells. However, the endothelial protective effects of DAPA were abolished when cells were subjected to the SIRT1 inhibitor (EX-527) and AMPK inhibitor (Compound C). These findings suggest that DAPA can abrogate HG-induced endothelial cell dysfunction by AMPK/SIRT1 pathway up-regulation. Therefore, suggesting that the activation of AMPK/SIRT1 axis by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury. This article is protected by copyright. All rights reserved.
    Keywords:  Dapagliflozin; HUVECs; High glucose; ROS; SIRT1
    DOI:  https://doi.org/10.1111/1440-1681.13638
  27. Atherosclerosis. 2022 Feb 16. pii: S0021-9150(22)00076-4. [Epub ahead of print]346 36-45
    Irisin alleviates vascular calcification by inhibiting VSMC osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling pathway in chronic kidney disease.
    Pei-Wen Wang, Qi Pang, Ting Zhou, Xin-Yu Song, Ya-Jing Pan, Lin-Pei Jia, Ai-Hua Zhang.
       BACKGROUND AND AIMS: Vascular calcification (VC) is an intricate active process, significantly controlled by vascular smooth muscle cells (VSMCs). Mitochondrial dysfunction plays a pivotal role in VC and VSMCs osteoblastic transformation. We previously reported that decreased levels of Irisin were independently associated with VC in hemodialysis patients. The present study aimed to investigate the role of Irisin in VC, especially in VSMCs osteoblastic transformation and mitochondrial function.
    METHODS: In vitro, VSMCs calcification was induced by β-glycerophosphate, while in vivo VC was triggered by adenine and high phosphorus diet. Alizarin red, Von Kossa staining, and calcium and Alp activity were performed to test VC. Western blot and immunohistochemical staining were employed to analyze the expression of proteins associated with VSMCs osteoblastic transformation and AMPK signaling. Mitochondrial membrane potential (MMP) and structures were observed by immunofluorescence staining.
    RESULTS: Irisin alleviated VSMCs calcification induced by β-glycerophosphate. Mechanistically, Irisin activated AMPK and downregulated the expression of Drp1, further alleviating mitochondria fission and VSMCs osteoblastic transformation. In vivo, Irisin decreased serum creatinine, urea and phosphorous levels in chronic kidney disease (CKD) mice. Importantly, Irisin treatment postponed CKD-associated VC with the upregulation of α-Sma and p-AMPK expression, and the downregulation of Runx2 and Drp1 expression.
    CONCLUSIONS: Our results firstly reveal that Irisin inhibits CKD-associated VC. Irisin suppresses VSMCs osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling.
    Keywords:  Chronic kidney disease; Irisin; Mitochondrial fission; Osteoblastic transformation; Vascular calcification
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.02.007
  28. Biochim Biophys Acta Mol Cell Res. 2022 Mar 07. pii: S0167-4889(22)00043-X. [Epub ahead of print] 119252
    Calcium/calmodulin-dependent protein kinase kinase 2 mediates pleiotropic effects of epidermal growth factor in cancer cells.
    Shuhang Dai, Elisa Venturini, Saveg Yadav, Xiaoxuan Lin, Dylan Clapp, Martin Steckiewicz, Angela M Gocher-Demske, D Grahame Hardie, Arthur M Edelman.
       AIMS: Engagement of epidermal growth factor (EGF) with its receptor (EGFR) produces a broad range of cancer phenotypes. The overriding aim of this study was to understand EGFR signaling and its regulation by the Ca2+/calmodulin (CaM) dependent protein kinase kinase 2 (CaMKK2) in cancer cells.
    RESULTS: In ovarian cancer cells and other cancer cell types, EGF-induced activation of oncogenic Akt is mediated by both the canonical PI3K-PDK1 pathway and by CaMKK2. Akt activation induced by EGF occurs by both calcium-dependent and calcium-independent mechanisms. In contrast to the canonical pathway, CaMKK2 neither binds to, nor is regulated by phosphoinositides but is activated by Ca2+/CaM. Akt activation at its primary activation site, T308 occurs by direct phosphorylation by CaMKK2, but activation at its secondary site (S473), is through an indirect mechanism requiring mTORC2. In cells in which another CaMKK2 target, 5'AMP-dependent protein kinase (AMPK) was deleted, Akt activation and calcium-dependency of activation were still observed. CaMKK2 accumulates in the nucleus in response to EGF and regulates transcription of phosphofructokinase platelet (PFKP) a glycolytic regulator. CaMKK2 is required for optimal PFK activity. CaMKK2 regulates transcription of plasminogen activator, urokinase (PLAU) a metastasis regulator. The EGFR inhibitor gefitinib synergizes with CaMKK2 inhibition in the regulation of cell survival and increases the dose-reduction index. CRISPR/Cas9 knockout of CaMKK2 leads to compensatory PTEN downregulation and upregulation of Akt activation.
    CONCLUSIONS: CaMKK2-mediation of EGFR action may enable cancer cells to use intracellular calcium elevation as a signal for growth and survival.
    Keywords:  Calcium; Calmodulin; Cancer; EGF; Kinase
    DOI:  https://doi.org/10.1016/j.bbamcr.2022.119252
  29. Food Funct. 2022 Mar 09.
    Dioscin relieves diabetic nephropathy via suppressing oxidative stress and apoptosis, and improving mitochondrial quality and quantity control.
    Yujie Zhong, Jiayu Liu, Dianjun Sun, Tianmin Guo, Yanpeng Yao, Xiaodong Xia, Chao Shi, Xiaoli Peng.
      Dioscin is a steroidal saponin isolated from various kinds of vegetables and herbs and possesses various biological activities. In this study, the protective effect of dioscin on diabetic nephropathy (DN) was explored. Dioscin and metformin (positive control) were administered orally to diabetic rats daily for 8 weeks. The biochemistry parameters, pancreas and kidney histological changes, oxidative stress, inflammation, apoptosis, autophagy, and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were measured. Our results showed that dioscin effectively reduced blood glucose, pancreatic injury, renal function markers and renal pathological changes in DN rat kidneys. Dioscin reduced O2- and H2O2 levels, decreased MDA levels, enhanced antioxidant enzyme (SOD, CAT) activities, and reduced inflammatory factor expressions. Moreover, NOX4 expression and the disorder of the mitochondrial respiratory chain were reversed by dioscin. Furthermore, apoptosis mediated by the mitochondria and ER stress was inhibited by dioscin through downregulating the expressions of Bax, CytC, Apaf-1, caspase 9, p-PERK, p-EIF2α, IRE1, p-IRE1, XBP1s, ATF4, p-CHOP and caspase 12. In addition, autophagy was enhanced by dioscin via an AMPK-mTOR pathway. Mitophagy and mitochondrial fission/fusion belong to the mitochondrial quality and quantity control process, which was improved by dioscin via regulating Parkin, PINK1, DRP1, p-DRP1 and MFN2 expressions. Collectively, these results suggested that dioscin protected against DN through inhibiting oxidative stress, inflammation, and apoptosis mediated by the mitochondria and ER stress. Autophagy and mitochondrial quality and quantity control (mitophagy and mitochondrial fission/fusion) were also improved by dioscin.
    DOI:  https://doi.org/10.1039/d1fo02733f
  30. Autophagy. 2022 Mar 08. 1-18
    Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.
    Silvia Magalhaes-Novais, Jan Blecha, Ravindra Naraine, Jana Mikesova, Pavel Abaffy, Alena Pecinova, Mirko Milosevic, Romana Bohuslavova, Jan Prochazka, Shawez Khan, Eliska Novotna, Radek Sindelka, Radek Machan, Mieke Dewerchin, Erik Vlcak, Joanna Kalucka, Sona Stemberkova Hubackova, Ales Benda, Jermaine Goveia, Tomas Mracek, Cyril Barinka, Peter Carmeliet, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.
      Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.
    Keywords:  ATG4B; biosynthesis; cell death; electron transport chain; endothelial cells; mitochondria; oxidative phosphorylation; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2022.2038898
  31. Cells. 2022 Mar 02. pii: 862. [Epub ahead of print]11(5):
    Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function.
    Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, Mohammad Alfatah.
      Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.
    Keywords:  AMPK; Saccharomyces cerevisiae; cellular lifespan extension; chronological aging; iron; mitochondria
    DOI:  https://doi.org/10.3390/cells11050862
  32. Phytomedicine. 2022 Feb 18. pii: S0944-7113(22)00085-X. [Epub ahead of print]99 154007
    Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway.
    Lianfang Liu, Tianya Liu, Weiwei Tao, Naikai Liao, Qiuying Yan, Liu Li, Jiani Tan, Weixing Shen, Haibo Cheng, Dongdong Sun.
       PURPOSE: Scutellaria barbata D. Don (SB), mainly containing flavonoids, has been frequently used for cancer treatment. However, little research has investigated the antitumor activity of flavonoids from SB (FSB). The current study aimed to assess the antitumor effect of TFSB and elucidate the probable underlying mechanism in vivo and in vitro.
    STUDY DESIGN: FSB was prepared, and its chemical composition was characterized by HPLC-MS. Colorectal HCT116 cells were treated with various concentration of FSB. The viability, proliferation, apoptosis, migration, and autophagy of HCT116 cells were studied, as were further confirmed in tumor xenografts.
    METHODS: Cell viability and proliferation were respectively examined by MTT and EdU staining. ROS was determined with DCFH-DA, and cell apoptosis was detected using flow cytometry. Transwell and wound-healing assays were performed to evaluate cell migration. Immunofluorescence was employed to evaluate sestrin2 and ATF4 level. The protein expressions of p-AMPK, p-ULK1, p-mTOR, 4E-BP1, LC3-I/II, cleaved-caspase-3, Bax, and bcl-2 were investigated by western blot. ATF4 was overexpressed in experiments to explore the role of ATF4/sestrin2 pathway in FSB-mediated efficacy.
    RESULTS: FSB clearly reduced the cell viability, promoted ROS generation, and induced apoptosis in HCT116 cells by down-regulated Bcl-2, and increased cleaved-caspase-3 and Bax. Furthermore, FSB significantly inhibited migration of colorectal cells in a dose-dependent manner. Further mechanistic study indicated that FSB upregulated p-mTOR protein level, and reduced p-AMPK, p-ULK1, p-mTOR, p-4E-BP1 and LC3-I/II expression, which were major autophagy-related genes. In addition, FSB could cause downregulation of endogenous mTOR inhibitor sestrin2 and ATF4 expression. Transient overexpression of ATF4 resulted in mTOR and sestrin2 inhibition, and significantly compromised the effects of FSB on apoptosis and autophagy in HCT116 cells.
    CONCLUSION: Our results reveal, for the first time, that FSB exerts antitumor activity through autophagy inhibition and apoptosis induction via ATF4/sestrin2 pathway in colorectal cancer cells. Scutellaria barbata D. Don may have great potential in the application for the prevention and treatment of human colorectal cancer.
    Keywords:  ATF4; Autophagy; Colorectal cancer; Scutellaria barbata D. Don; apoptosis; sestrin2
    DOI:  https://doi.org/10.1016/j.phymed.2022.154007
  33. Phytomedicine. 2022 Mar 04. pii: S0944-7113(22)00109-X. [Epub ahead of print]99 154031
    Therapeutic effect and mechanism of polysaccharides from Anoectochilus Roxburghii (Wall.) Lindl. in diet-induced obesity.
    Dongmei Tian, Xiaoyan Zhong, Liya Fu, Wanlong Zhu, Xin Liu, Zhigui Wu, Yue Li, Xue Li, Xuesen Li, Xuemei Tao, Qiming Wei, Xuping Yang, Yilan Huang.
       BACKGROUND: Recent studies have shown that polysaccharides from Anoectochilus roxburghii (Wall.) Lindl. (ARPs) can reduce blood glucose levels, ameliorate oxidative stress and inflammation. However, whether ARPs have a beneficial effect on diet-induced obesity remain to be determined.
    PURPOSE: This study aims to investigate the effect and mechanism of ARPs in improving obesity and metabolic disorders induced by high-fat diet (HFD).
    METHODS: In this study, 6-week-old male mice were fed with HFD or chow diet for 13 weeks, and a dietary supplementation with ARPs was carried out. Glucose tolerance test and insulin tolerance test were performed to measure the glucose tolerance and insulin sensitivity. Adipose tissue and liver were isolated for analysis by qRT-PCR, Western blotting, hematoxylin-eosin staining and immunostaining.
    RESULTS: At week 13, body weight and fat mass were significantly increased by HFD, but ARPs supplementation abolished these phenotypes. Compared with HFD group, thermogenic genes including Ucp-1, Pgc-1α, Prdm16 and Dio2 in adipose tissue were up-regulated in ARPs-treated mice. In addition, ARPs decreased liver lipid accumulation by reducing lipid synthesis and increasing oxidation. Meanwhile, dyslipidemia and insulin resistance induced by HFD were improved by ARPs. Mechanistically, ARPs can promote fat thermogenesis via AMPK/SIRT1/PGC-1α signaling pathway.
    CONCLUSION: Dietary supplementation of ARPs can protect mice against diet-induced obesity, fatty liver and insulin resistance. Our study reveals a potential therapeutic effect for ARPs in regulating energy homeostasis.
    Keywords:  Anoectochilus roxburghii polysaccharides; Energy metabolism; Metabolic disorders; Non-alcoholic fatty liver disease; Obesity
    DOI:  https://doi.org/10.1016/j.phymed.2022.154031
  34. Free Radic Biol Med. 2022 Mar 07. pii: S0891-5849(22)00097-1. [Epub ahead of print]
    TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway.
    Min-Yao Liu, Hong-Ming Li, Xin-Yu Wang, Ran Xia, Xiang Li, Yu-Jie Ma, Miao Wang, Hong-Sheng Zhang.
      Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and major cause of cancer death in the world. Ferroptosis is a recently identified type of regulated cell death. Increasing evidence has shown that ferroptosis plays an important regulatory role in the occurrence and development of cancer. This study identified TIGAR as a potential regulator of ferroptosis resistance in the development of CRC. We showed that TIGAR expression in CRC tissues is significantly higher than that in adjacent normal tissues. Knockdown of TIGAR significantly caused an increase in erastin-induced ferroptosis in SW620 and HCT116 cells. Notably, knockdown of TIGAR significantly decreased GSH/GSSG ratio, increased lipid peroxidation production, and facilitated the accumulation of lipid peroxidation product malondialdehyde (MDA), and rendered CRC cells more sensitive to erastin induced ferroptosis. Furthermore, TIGAR inhibition repressed SCD1 expression in a redox and AMPK-dependent manner. Thus, these results suggest that TIGAR induces ferroptosis resistance in CRC cells via the ROS/AMPK/SCD1 signaling pathway.
    Keywords:  AMPK; Ferroptosis; Redox; SCD1; TIGAR
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.03.002
  35. Biomed Pharmacother. 2022 Mar 02. pii: S0753-3322(22)00159-7. [Epub ahead of print]148 112771
    Recent update on application of dihydromyricetin in metabolic related diseases.
    Yirong Wang, Junmin Wang, Hongjiao Xiang, Peilun Ding, Tao Wu, Guang Ji.
      As a new type of natural flavonoids, dihydromyricetin (DMY) has attracted more and more attention. It has a series of pharmacological effects, such as anti-inflammatory, anti-tumor, anti-oxidation, antibacterial and so on, and it is almost no toxicity and with excellent safety. Therefore, even if the bioavailability is poor, it is often added to daily food, beverages and even medicines. In recent years, some researchers have found that DMY can treat some diseases by anti-oxidation, anti-inflammation, promoting cell death and regulate the activity of lipid and glucose metabolism. In addition, the mechanism of DMY on these diseases was also related to the signal pathway of AMPK, PI3K/Akt, PPAR and the participation of microRNAs. This review describes the mechanism of DMY in metabolic related diseases from three aspects: metabolic diseases, liver diseases, and cancers, hoping to provide some new ideas for clinical researches.
    Keywords:  Cancers; Dihydromyricetin; Liver diseases; Metabolic diseases
    DOI:  https://doi.org/10.1016/j.biopha.2022.112771
  36. Front Nutr. 2022 ;9 802015
    Molecular Mechanism Underlying the Regulatory Effect of Vine Tea on Metabolic Syndrome by Targeting Redox Balance and Gut Microbiota.
    Xixin Zhou, Ying Song, Chaoxi Zeng, Haowei Zhang, Chenghao Lv, Meng Shi, Si Qin.
      Metabolic syndrome (MS) is a metabolic disorder that arises from the increasing prevalence of obesity. The pathophysiology seems to be largely attributable to the imbalance of lipid and glucose metabolism, redox signaling pathways, and gut microbiota. The increased syndromes, such as type 2 diabetes and cardiovascular disease demands natural therapeutic attention for those at high risk. Vine tea, as a traditional medicinal and edible resource rich in flavonoids, especially for dihydromyricetin (DHM), exhibits promising health benefits on the intervention of MS, but the specific molecular mechanism has not been systematically elucidated. The present article aims to summarize the regulatory effects and biological targets of vine tea or DHM on MS, and analyze the underlying potential molecular mechanisms in cells, animals, and humans, mainly by regulating the redox associated signaling pathways, such as Nrf2, NF-κB, PI3K/IRS2/AKT, AMPK-PGC1α-SIRT1, SIRT3 pathways, and the crosstalk among them, and by targeting several key biomarkers. Moreover, vine tea extract or DHM has a positive impact on the modulation of intestinal microecology by upregulating the ratio of Firmicutes/Bacteroidetes (F/B) and increasing the relative abundance of Akkermansia muciniphila. Therefore, this review updated the latest important theoretical basis and molecular evidence for the development and application of vine tea in dietary functional products or drugs against MS and also imputed the future perspectives to clarify the deep mechanism among vine tea or DHM, redox associated signaling pathways, and gut microbiota.
    Keywords:  biotransformation; dihydromyricetin; gut microbiota; metabolic syndrome; redox signaling pathway
    DOI:  https://doi.org/10.3389/fnut.2022.802015
  37. Nutrients. 2022 Mar 05. pii: 1097. [Epub ahead of print]14(5):
    (-)-Epicatechin Improves Vasoreactivity and Mitochondrial Respiration in Thermoneutral-Housed Wistar Rat Vasculature.
    Ji Hye Chun, Melissa M Henckel, Leslie A Knaub, Sara E Hull, Greg B Pott, Lori A Walker, Jane E-B Reusch, Amy C Keller.
      Cardiovascular disease (CVD) is a global health concern. Vascular dysfunction is an aspect of CVD, and novel treatments targeting vascular physiology are necessary. In the endothelium, eNOS regulates vasodilation and mitochondrial function; both are disrupted in CVD. (-)-Epicatechin, a botanical compound known for its vasodilatory, eNOS, and mitochondrial-stimulating properties, is a potential therapy in those with CVD. We hypothesized that (-)-epicatechin would support eNOS activity and mitochondrial respiration, leading to improved vasoreactivity in a thermoneutral-derived rat model of vascular dysfunction. We housed Wistar rats at room temperature or in thermoneutral conditions for a total of 16 week and treated them with 1mg/kg body weight (-)-epicatechin for 15 day. Vasoreactivity, eNOS activity, and mitochondrial respiration were measured, in addition to the protein expression of upstream cellular signaling molecules including AMPK and CaMKII. We observed a significant improvement of vasodilation in those housed in thermoneutrality and treated with (-)-epicatechin (p < 0.05), as well as dampened mitochondrial respiration (p < 0.05). AMPK and CaMKIIα and β expression were lessened with (-)-epicatechin treatment in those housed at thermoneutrality (p < 0.05). The opposite was observed with animals housed at room temperature supplemented with (-)-epicatechin. These data illustrate a context-dependent vascular response to (-)-epicatechin, a candidate for CVD therapeutic development.
    Keywords:  cardiovascular disease; eNOS; vascular
    DOI:  https://doi.org/10.3390/nu14051097
  38. Cancers (Basel). 2022 Mar 05. pii: 1343. [Epub ahead of print]14(5):
    Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells.
    Jernej Repas, Mateja Zupin, Maja Vodlan, Peter Veranič, Boris Gole, Uroš Potočnik, Mojca Pavlin.
      Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC.
    Keywords:  2-deoxy-D-glucose; AMPK; ER stress; PD-1/PD-L1 axis; T cells; anchorage-independence; metformin; mitochondrial biogenesis; protein N-glycosylation; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers14051343
  39. Nutrients. 2022 Jan 20. pii: 454. [Epub ahead of print]14(3):
    Short-Term Adaptations in Skeletal Muscle Mitochondrial Oxidative Capacity and Metabolic Pathways to Breaking up Sedentary Behaviors in Overweight or Obese Adults.
    Nathan P De Jong, Michael C Rudolph, Matthew R Jackman, Rachel R Sharp, Ken Jones, Julie Houck, Zhaoxing Pan, Jane E B Reusch, Paul S MacLean, Daniel H Bessesen, Audrey Bergouignan.
      Breaking up sedentary behavior with short-frequent bouts of physical activity (PA) differentially influences metabolic health compared with the performance of a single-continuous bout of PA matched for total active time. However, the underlying mechanisms are unknown. We compared skeletal muscle mitochondrial respiration (high-resolution respirometry) and molecular adaptations (RNA sequencing) following 4-day exposure to breaks vs. energy-matched single-continuous PA bout in inactive adults with overweight/obesity. Participants (9M/10F, 32.2 ± 6.4 years, 30.3 ± 3.0 kg/m2) completed three 4-day interventions of a randomized cross-over study: SED, sedentary control; MICRO, 5 min brisk walking each hour for 9 h; ONE: 45 min/d continuous brisk walking bout. Fasted muscle biopsies were collected on day 5. Mitochondrial coupling in the presence of lipid-associated substrates was higher after ONE (4.8 ± 2.5) compared to MICRO (3.1 ± 1.1, p = 0.02) and SED (2.3 ± 1.0, p = 0.001). Respiratory rates did not differ across groups with carbohydrate-associated substrates. In pathways associated with muscle contraction transcription signaling, ONE and MICRO similarly enhanced Oxidative Phosphorylation and Sirtuin Signaling expression (p < 0.0001, for both). However, ONE (p < 0.001, for all), but not MICRO, had greater pathway enrichment, including Ca++, mTOR, AMPK, and HIF1α signaling, than SED. Although breaking up sedentary behavior triggered skeletal muscle molecular adaptations favoring oxidative capacity, it did not improve mitochondrial function over the short term.
    Keywords:  active breaks; mRNA sequencing; mitochondria; obesity; sedentary behavior; skeletal muscle molecular adaptations
    DOI:  https://doi.org/10.3390/nu14030454
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